CN101925591A - Process for production of cyclic diesters of alpha-hydroxyacids - Google Patents
Process for production of cyclic diesters of alpha-hydroxyacids Download PDFInfo
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- CN101925591A CN101925591A CN2008801256751A CN200880125675A CN101925591A CN 101925591 A CN101925591 A CN 101925591A CN 2008801256751 A CN2008801256751 A CN 2008801256751A CN 200880125675 A CN200880125675 A CN 200880125675A CN 101925591 A CN101925591 A CN 101925591A
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- alpha
- hydroxy acid
- alkaline earth
- salt
- acid
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- 229940061720 alpha hydroxy acid Drugs 0.000 title claims abstract description 46
- 150000001280 alpha hydroxy acids Chemical class 0.000 title claims abstract description 45
- 238000000034 method Methods 0.000 title claims abstract description 41
- -1 cyclic diesters Chemical class 0.000 title claims abstract description 23
- 238000004519 manufacturing process Methods 0.000 title description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000007787 solid Substances 0.000 claims abstract description 19
- 238000002425 crystallisation Methods 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims abstract description 12
- 239000000203 mixture Substances 0.000 claims abstract description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 69
- 239000004310 lactic acid Substances 0.000 claims description 33
- 235000014655 lactic acid Nutrition 0.000 claims description 33
- 239000000243 solution Substances 0.000 claims description 30
- 230000036571 hydration Effects 0.000 claims description 18
- 238000006703 hydration reaction Methods 0.000 claims description 18
- 238000000197 pyrolysis Methods 0.000 claims description 16
- 241000894006 Bacteria Species 0.000 claims description 11
- 229910052749 magnesium Inorganic materials 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 8
- 239000012452 mother liquor Substances 0.000 claims description 8
- 238000001556 precipitation Methods 0.000 claims description 8
- 238000004821 distillation Methods 0.000 claims description 7
- 238000001704 evaporation Methods 0.000 claims description 7
- 238000000855 fermentation Methods 0.000 claims description 7
- 230000004151 fermentation Effects 0.000 claims description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 230000008020 evaporation Effects 0.000 claims description 6
- 239000012535 impurity Substances 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 150000005690 diesters Chemical class 0.000 claims description 4
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 claims description 4
- 239000012429 reaction media Substances 0.000 claims description 3
- 230000035900 sweating Effects 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 238000011065 in-situ storage Methods 0.000 claims description 2
- 238000001172 liquid--solid extraction Methods 0.000 claims description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 2
- 229960002510 mandelic acid Drugs 0.000 claims description 2
- 238000006386 neutralization reaction Methods 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims 1
- 229910052742 iron Inorganic materials 0.000 claims 1
- 239000000539 dimer Substances 0.000 abstract description 3
- 239000002244 precipitate Substances 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 239000011777 magnesium Substances 0.000 description 20
- 235000015229 magnesium lactate Nutrition 0.000 description 14
- OVGXLJDWSLQDRT-UHFFFAOYSA-L magnesium lactate Chemical compound [Mg+2].CC(O)C([O-])=O.CC(O)C([O-])=O OVGXLJDWSLQDRT-UHFFFAOYSA-L 0.000 description 13
- 229920000747 poly(lactic acid) Polymers 0.000 description 11
- 239000000626 magnesium lactate Substances 0.000 description 10
- 229960004658 magnesium lactate Drugs 0.000 description 10
- MNKRTDOUBUSQHX-UHFFFAOYSA-N 2,4-dihydroxy-2-methyl-3-oxopentanoic acid Chemical compound CC(O)C(=O)C(C)(O)C(O)=O MNKRTDOUBUSQHX-UHFFFAOYSA-N 0.000 description 9
- 229940091250 magnesium supplement Drugs 0.000 description 9
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 238000005119 centrifugation Methods 0.000 description 5
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 5
- 239000000347 magnesium hydroxide Substances 0.000 description 5
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 150000008064 anhydrides Chemical class 0.000 description 4
- 230000018044 dehydration Effects 0.000 description 4
- 238000006297 dehydration reaction Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000002699 waste material Substances 0.000 description 4
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 description 3
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 3
- 229920000954 Polyglycolide Polymers 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 description 3
- 239000001527 calcium lactate Substances 0.000 description 3
- 229960002401 calcium lactate Drugs 0.000 description 3
- 235000011086 calcium lactate Nutrition 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000006340 racemization Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000006200 vaporizer Substances 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- PASHVRUKOFIRIK-UHFFFAOYSA-L calcium sulfate dihydrate Chemical compound O.O.[Ca+2].[O-]S([O-])(=O)=O PASHVRUKOFIRIK-UHFFFAOYSA-L 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000006471 dimerization reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 description 2
- 238000012262 fermentative production Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000005484 gravity Effects 0.000 description 2
- 229910052602 gypsum Inorganic materials 0.000 description 2
- 239000010440 gypsum Substances 0.000 description 2
- 239000002815 homogeneous catalyst Substances 0.000 description 2
- 150000001261 hydroxy acids Chemical class 0.000 description 2
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 description 2
- 238000000622 liquid--liquid extraction Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 150000004684 trihydrates Chemical class 0.000 description 2
- RLKALOGJUOZZNA-UHFFFAOYSA-N 2-hydroxypropanoic acid;magnesium Chemical compound [Mg].CC(O)C(O)=O RLKALOGJUOZZNA-UHFFFAOYSA-N 0.000 description 1
- JJTUDXZGHPGLLC-IMJSIDKUSA-N 4511-42-6 Chemical compound C[C@@H]1OC(=O)[C@H](C)OC1=O JJTUDXZGHPGLLC-IMJSIDKUSA-N 0.000 description 1
- UDXQTTCYUTYYOO-UHFFFAOYSA-M C(C(O)C)(=O)[O-].C(C(O)C)(=O)[Mg+] Chemical compound C(C(O)C)(=O)[O-].C(C(O)C)(=O)[Mg+] UDXQTTCYUTYYOO-UHFFFAOYSA-M 0.000 description 1
- 101100246550 Caenorhabditis elegans pyr-1 gene Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 208000034530 PLAA-associated neurodevelopmental disease Diseases 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229940057801 calcium lactate pentahydrate Drugs 0.000 description 1
- JCFHGKRSYPTRSS-UHFFFAOYSA-N calcium;2-hydroxypropanoic acid;hydrate Chemical compound O.[Ca].CC(O)C(O)=O JCFHGKRSYPTRSS-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000000909 electrodialysis Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 229940116333 ethyl lactate Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000003903 lactic acid esters Chemical class 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229920000139 polyethylene terephthalate Polymers 0.000 description 1
- 239000005020 polyethylene terephthalate Substances 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000012667 polymer degradation Methods 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000007151 ring opening polymerisation reaction Methods 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 238000000956 solid--liquid extraction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 239000012808 vapor phase Substances 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/12—1,4-Dioxanes; Hydrogenated 1,4-dioxanes not condensed with other rings
Abstract
Process for the synthesis of a cyclic diester of an alpha-hydroxyacid, comprising the following steps: an alkalino-earth salt of the corresponding alpha-hydroxyacid is mixed with said alpha-hydroxyacid and water; the mixture is treated by evaporation-crystallization, so that a hydrate of the alkalino-earth salt of the linear dimer of the corresponding alpha-hydroxiacid precipitates; the hydrated salt is dehydrated to give the corresponding anhydrous salt; and the anhydrous salt is pyrolyzed, releasing the cyclic diester of the corresponding alpha-hydroxyacid and leaving the alkalino-earth hydroxide as solid residue.
Description
The application requires the right of priority of the U. S. application submitted on December 26th, 2007 number 61/008,654, by reference it is combined in this.
The synthetic lactic acid pure on the enantiomer meaning (LA) that used of the poly(lactic acid) (PLA) of great majority report is as raw material.Because it is reproducible being used for the raw material of synthetic LA, so (Drumright et al., " Polylactic Acid Technology " are slowly developed in the commercial production of this Biodegradable polymeric, 2000, Adv.Mater., v.12, pp.1841-1846).
Its application in field of medicaments might be controlled a high price fully, but if it will compete successfully with fossil oil derived polymers such as polystyrene (those mechanical characteristicies of its multiple mechanical characteristics and PLA are quite similar) or polyethylene terephthalate (being used for a bottle class), then its production cost minimizing of having to.
The building-up reactions of PLA is a kind of ring-opening polymerization (U.S. Patent number 5,319,107) of rac-Lactide (LD) in the presence of a kind of homogeneous catalyst.As if these reaction conditionss are well-known now, and be difficult to obtain better quality product or littler energy expenditure in this step.
On the contrary, the production technique of the classics of (cyclic diester LD) has been full of difficulty from LA to the key intermediate.
Some steps in this classical way come down to single step evaporation (under low pressure) and mean removal solution water or condensation reaction water, as finding out from following explanation:
A.-is at Ca (OH)
2(or CaCO
3) existence under, a kind of selected carbohydrate causes bacterium at a kind of calcium lactate (CaLac by the fermentation of selected bacterium
2) a kind of generation of suspension in the solution.
B.-with these bacteriums by centrifugal or filter and to separate and abandon (Application No. 5,766,439).
C.-makes this filtrate and sulfuric acid reaction, and this causes that the precipitation of gypsum (calcium sulphate dihydrate) and lactic acid (LA) are as certain release (Application No. 20050281913) of a kind of solution of 10% by weight.
D.-is concentrated into the LA of 85%-88% by weight with the sort of solution by distillation.
E.-makes this spissated LA solution stand a kind of prepolymerization reaction in the presence of a kind of homogeneous catalyst, in a kind of vacuum distillation column, and wherein more water is separated.
F.-is because the molecular weight of this prepolymer only is about 1000, so its mechanical characteristics is not suitable for industrial application.
G.-carries out depolymerization by inventing a charge against (back-biting) with this prepolymer then under vacuum in the presence of a kind of selected catalyzer, and will stay the LD that is in vapor phase in this reactor is condensed into a kind of liquid or is fed directly in the distillation column to produce liquid crude LD (mixing mutually with the undesired enantiomer of LA, some its light oligopolymer, water, LD etc.) (U.S. Patent number 5,357,035).
H.-should thick LD carries out liquid-liquid extraction by water and is further purified the crystallization from the aqueous solution that continues (Application No. 20060014975).
The i.-centrifugation has provided the cake piece of the LD of a purifying, but because impurity level is still too big, requires to have a last operation:
J.-carries out melt crystallization to remove these impurity by gravity flowage by perspiration.
All these operations all are well-known, make like this to produce the enantiomer L-LD that for example has up to 99.9% purity.But the output to the certain operations of this long-chain is quite limited, like this, requires a plurality of big recirculation flow, and like this, it is very big that different equipment spares is tending towards, thereby very big energy requirement is arranged.
Big development efforts has been devoted to the improvement of classical LD production technique, promptly therein technology (the Rathin Datta of lactic acid as raw material, " Technological and economicpotential of poly (lactic acid) and lactic acid derivatives ", 1995, FEMSMicrobiology Reviews, v.16, pp.221-231).For example, liquid-liquid extraction method is compared with evaporation of water to provide and is required the lower mode of degree to be used for concentrating of LA on a kind of energy, but the solvent of eliminating trace fully is still a problem.More advanced isolation technique (as the electrodialysis of ethyl lactate) is likely.
In classic methods, produced a large amount of waste product (calcium sulphate dihydrate or gypsum).
Can be similarly with other alpha-hydroxy acid class, as oxyacetic acid (GA) dimerization for this corresponding cyclic diester and therefore by identical method and to follow same shortcoming dimerization be that polyprotonic acid (for example, obtains polyglycolic acid by glycollide, PGA).
Although there are these obstacles, but PLA (and PGA) might become a kind of commodity fully, make like this a kind of possibility of problem must address the disposal of a large amount of rejected material (as, empty bottle class) or to utilize again be by heating 300 ℃ of left and right sides depolymerization, generate the LD steam and it condensed.This method is very simple, but the racemization under such high temperature has reduced the purity of the optically active isomer of this product.In order to avoid this last difficulty, people can carry out depolymerization (Toru Motoyama by pyrolysis with CaO or MgO powder mixes to PLA and under lower temperature, " Effects of MgO catalyst on depolymerization ofpoly-L-lactic acid to L; L-lactide ", 2007, Polymer Degradation andStability, v.92, pp.1350-1358).
Especially relevant with the present invention is following comment suggestion, that is: the molecular weight that has when these MgO particulate sizes reduce is that the depolymerization temperature (and degree of racemization) of 170000 PLA reduces (Toru Motoyama, Fig. 2 and Fig. 3 in 2007) regularly.It should be noted that the following fact equally, that is: the weight of MgO is represented 5% (as Mg) of the weight of PLA in described reference.
The on the other hand magnesium hydroxide of in prior art, paying close attention to (Mg (OH)
2) will be only in higher temperature (about 400 ℃) dehydration down.
The linear dimer of the on the other hand LA that in prior art, pays close attention to, be lactyllactic acid (LacOLacA), be a kind of acid stronger (Bezzi, S., " I produtti dianidrificazione dell ' acido lattico come tipo delle trasformazioni degliesteri ciclici in poliesteri lineari " than LA, 1937, Mem.reale acad.Italia, Classesci.fis., mat.e nat., v.8, pp.127-213).
Know already by fermenting lactic acid magnesium (MgLac
2) and produce CaLac
2Equally easy (Application No. 3,429,777).In addition, because MgLac
2Solubleness to a certain extent greater than CaLac
2Solubleness, so if this lactate is to be undertaken by crystallization that isolating then the former may have advantage.
If may be calcium lactate or magnesium lactate directly from the LA raw material, directly arrive this LD, the vestige of the depolymerization catalyzer of then remaining trace extraction solvent, trace does not have problems, and the cost of the product of PLA may reduce.
(temporary patent application 60/874 in a patent application before, 475), I have disclosed a kind of method, this method realizes these purposes by introduce multiple anhydrous response thing (as anhydrous calcium lactate and sulphuric anhydride) in this LD production reactor, like this, this organic products will dewater under the condition of gentleness in the operation before.
The waste products that obtains in described method can still not have a kind of method of waste products with more attractive in industrial use.A kind of like this method of not having waste is a purpose of the present invention.
The brief overview of invention
The present invention relates to a kind of method that is used for the cyclic diester of synthetic alpha-hydroxy acid, may further comprise the steps:
-correspondence is divided the alkaline earth salt of alpha-hydroxy acid mix with described alpha-hydroxy acid and water;
-mixture to be handled by evaporate-crystallization, the hydrate of the linear dimeric alkaline earth salt of the alpha-hydroxy acid of feasible like this correspondence produces precipitation;
-salt of hydration is dewatered to provide corresponding anhydrous; And
-with this anhydrous salt pyrolysis (preferably in the presence of water vapour or inert support), thus discharge the cyclic diester of this corresponding alpha-hydroxy acid and stay this alkaline earth hydroxide as solid residue.
This resistates can and then be used for a kind of method, and wherein the fermentation of the sugar of the alkaline earth salt of this alpha-hydroxy acid by carrying out in the presence of the bacterium natural carbohydrate of fruits, plant class, milk preparation class etc. (preferably from) is produced.That is, making this fermentation process requirement alkaline pH like this, like this, is that a kind of alkaline earth hydroxide is added in this reaction medium generally.
Therefore the alpha-hydroxy acid of the method according to this invention can be by obtainable any this type of acid of fermenting, as lactic acid, oxyacetic acid, pentanedioic acid, amygdalic acid, oxysuccinic acid, citric acid or tartrate, and preferred preceding 2.The present invention has provided good effect with lactic acid.
As for this alkaline-earth metal, preferentially be selected from: select preferred preceding 2 between Mg, Ca, Zn, Al and the Fe.
The alkaline earth salt of alpha-hydroxy acid class is commercially available under the form of hydration generally.For example, two hydration magnesium lactates are in trade(brand)name
Obtainable under the MG.
Spendable in the method for the invention alpha-hydroxy acid class also can be purchased; For example, a kind of 80% lactic acid aqueous solution is obtainable under trade(brand)name PURAC FCC80.
Replace using a kind of commercial alpha-hydroxy acid, according to one embodiment of the invention, described alpha-hydroxy acid is to carry out pyrolysis by a kind of alkaline earth salt that makes described alpha-hydroxy acid to obtain in the presence of water.In a preferred embodiment, therefore method wherein of the present invention combines with a kind of fermentation process of as above explanation, makes end reaction medium half (comprise this alpha-hydroxy acid alkaline earth salt) stand pyrolysis to provide this corresponding alpha-hydroxy acid form of steam (generally with) and alkaline earth hydroxide in the presence of water.
Therefore, the invention still further relates to a kind of synthetic method that is used for the cyclic diester of alpha-hydroxy acid class, wherein unique principal reaction thing is a kind of aqueous solution of a kind of alkaline earth salt of this corresponding alpha-hydroxy acid.
In the method, this aqueous solution is preferably at first spissated by evaporating.Then pact that preferably will described spissated solution half cool off, make a kind of hydrate of alkaline earth salt of this correspondence alpha-hydroxy acid produce like this and precipitate.
Preferably the salt of this hydration is separated from its mother liquor then, and further dewatered to provide this corresponding anhydrous.
Preferably with the anhydrous salt that obtains under the temperature of gentleness (typically, 250 ℃ down or lower) pyrolysis in the presence of water vapour, thereby discharge this alpha-hydroxy acid and stay this alkaline earth hydroxide as steam as solid residue.
With this alpha-hydroxy acid steam this spissated solution the second half in absorb, and it is handled by evaporate-crystallization, make a kind of hydrate of linear dimeric alkaline earth salt of this correspondence alpha-hydroxy acid produce precipitation like this.The salt of this hydration can be separated from its mother liquor then, and further be dewatered to provide this corresponding anhydrous.
Then with this salt at (350 ℃ or lower) under the temperature of gentleness, preferably in the presence of water vapour or a kind of inert support, advantageously carry out pyrolysis, thereby discharge the cyclic diester of this correspondence alpha-hydroxy acid and stay alkaline earth hydroxide as steam as solid residue.
This alkaline earth hydroxide can be recycled in the fermentor tank or to an alpha-hydroxy acid neutralization reactor then.
In this embodiment, the steam of the cyclic diester of alpha-hydroxy acid is optionally sublimated (condensing) and carry out in-situ purification by sweating, these impurity are mainly by evaporative removal.
For diester class (its volatility is low-down), this separating step can be replaced the crystallization from solution that continues with one or more liquid-solid extraction steps.
This preferred embodiment will be showed as a kind of particular case by way of example following.
The raw material that is used to produce LD is a kind of magnesium lactate solution, for example magnesium hydroxide, adaptive bacterium and be used for described bacterium nutriment in the presence of fermentative production by sugar.The bacterium in this nutrient solution that leaves this fermentor tank is separated (for example passing through centrifugation) and the liquid that will generate concentrates to provide a kind of spissated solution of magnesium lactate.This solution is divided into the stream of two equalizations, is used for further processing.
In order to be settled out a kind of hydrate (for example three hydration magnesium lactates), half that makes this magnesium lactate solution stands crystallisation by cooling.The salt of this hydration is under atmospheric pressure dewatered, thereby cause the magnesium lactate anhydride.With latter's pyrolysis that under the temperature in gentleness in the presence of the water vapour, (is lower than 250 ℃) and discharge the LA steam, thereby stay Mg (OH)
2A kind of solid residue.
The LA steam that will in step before, produce this magnesium lactate solution the second half in concentrate.The controlled evaporate-crystallization of this mixture causes and forms lactyllactic acid salt (Lactoyllacte) ion and cause the lactyllactic acid magnesium crystal of hydration to produce precipitation in solution.The salt of this hydration is under atmospheric pressure dewatered, thereby obtain lactyllactic acid magnesium anhydride.With the latter preferably in (but being lower than 350 ℃) pyrolysis in the presence of water vapour or a kind of inert support and under higher to a certain degree temperature and discharge the LD steam to avoid racemization, thereby stay Mg (OH)
2A kind of solid residue.The pure lactic acid of any obtainable commercial source can also use all magnesium lactates that passes through the fermentation generation to be used for producing lactyllactic acid magnesium apparently.
Detailed description of the invention
To describe by the specific embodiments of reference accompanying drawing now method of the present invention.
Preceding two steps are classical:
A.-selected carbohydrate is at Mg (OH)
2Existence under fermentation (at the fermentor tank F of the left upper of this figure) cause having produced bacterium at a kind of magnesium lactate (MgLac
2) a kind of suspension in the solution.
B.-separates these bacteriums and abandons by centrifugal (decanting vessel-whizzer DC) or filtration
Next step is similar at U.S. Patent number 5,766, that step that discloses in 439:
C.-is this filtrate (or enriched material (centrate)), a kind of solution of magnesium lactate, and (vaporizer E) concentrates by evaporation of water.
In first post, with half of this concentrated solution as at U.S. Patent number 5,766, in following two steps, further the handling of explanation in 439:
D.-crystallisation by cooling (device CC) causes the separation of a kind of hydrate (then is trihydrate if Tc is enough hanged down) of magnesium lactate.
E.-is by centrifugation (strainer-whizzer FC
1) with these crystal separation; This mother liquor further handled be used to separate more three hydration MgLac
2(MgLac
2TH) and separate a kind of solution of releasing.
Following steps have embodied purport of the present invention:
F.-makes this trihydrate under atmospheric pressure and under less than 150 ℃ temperature slowly dewater (baking oven DH1) to obtain anhydrous MgLac
2(for CaLac
2It is similar situation, referring to Yukoho Sakata et al., " Characterization of dehydration and hydrationbehaviour of calcium lactate pentahydrate and its anhydrate ", 2005, Colloids and Surfaces B:Biointerfaces, v.46, pp.135-141).
G.-is in the presence of water vapour, for producing under the sufficiently high temperature of LA steam (less than 250 ℃) and preventing remaining Mg (OH)
2Make this anhydrous MgLac under the enough low temperature of decomposing
2(reactor PyR1) pyrolysis.If the commercial lactic acid with enough purity is obtainable, then it can be used for that following steps replace as and lactic acid that produce illustrated at this.
Parallel therewith is,
The spissated MgLac that the LA steam that H.-generated generates in vaporizer E
2The residue of solution absorbs the lactyllactic acid magnesium (MgLacOLac of a kind of hydration that continues in half
2.nH
2O) condensation reaction and crystallization (in vaporizer-crystallizer EC).
I.-is by centrifugation (strainer-whizzer FC
2) with these crystal separation; Mother liquor 2 further processing are used to separate more hydration MgLacOLac
2And separate a kind of solution of releasing.
J.-is with the lactyllactic acid magnesium of hydration (the baking oven DH that under atmospheric pressure dewaters
2) to obtain anhydrous lactoyl magnesium lactate (MgLacOLac
2).
K.-preferably in the presence of water vapour or a kind of inert support for generating under the sufficiently high temperature of LD steam (less than 350 ℃) and preventing remaining Mg (OH)
2Make this anhydrous MgLacOLac under the enough low temperature of decomposing
2(reactor PyR
2) pyrolysis.This is similar to the pyrolysis (ToruMotoyama, 2007) of PLA, and wherein Mg approaches 5% (8.3%) with the ratio of lactic acid salt, and has the dispersion for the possible final degree of Mg.
Last three steps are borrowed in United States Patent (USP) provisional application 60/874,475 (its content is attached among the application by reference):
L-is under the temperature control of strictness, and LD optionally sublimates on many vertical pipes of a heat exchanger as a kind of columniform solid layer.
M.-reheats this layer to induce " sweating ", will generate a kind of impure viscous soln like this, but with in the melt crystallization device, take place opposite, these impurity will be by optionally distilling and not being drained by gravity.
The last step of N.-is similar to that step in melt crystallization, promptly discharges by the crystalline that melts these purifying of this layer fully.
Solid residue in two shunt of this method is Mg (OH)
2It is recirculated in the fermentor tank, like this, and except excessive bacterium and from this two strainers-whizzer FC
1And FC
2In mother liquor in outside the isolating impurity, this method does not stay solid waste.
The requirement of the energy of main heat is to be used for vaporizer E.In view of boiling point gentle in the magnesium lactate solution rises, might use a kind of multiple-effect evaporator, this will limit the cost (but having increased cost of investment) of energy.
Those of ordinary skill in the art will be clear that the elimination (by multiple-effect evaporation or by dehydration, rather than the vacuum distilling by habitually practising traditionally) of most of water under mild conditions is praiseworthy economically.In addition, in pyrolytic process, once generated LA (at PyR
1In) or LD (at PyR
2In) then with they evaporations, almost have no chance to be created in the big coacervate of magnesium hydroxide powder general in each reactor like this for these thick liquids (fusing point of LA and LD is respectively 42 ℃ and 98 ℃).
Those of ordinary skill in the art also is noted that, is possible by present method from the synthetic glycollide (GD) of GA (be not with fermentative Production): a first step, to make the reaction of GA solution and reactive magnesium hydroxide, and obtain a kind of solution of oxyacetic acid magnesium and duplicate rest part from this explanation of above step B.
Those of ordinary skill in the art also be noted that volatility more circlet diester class (as Mandelide) will be still can be by above explanation a kind of variant of method produce.Really, if by distillation and from this hydroxy acid on the one hand and sublimate the corresponding anhydride class of this cyclic diester on the other hand to separate and be not actual economically, still can be under correspondingly near the temperature of this hydroxy acid and this diester fusing point by a kind of suitable solvent (for example toluene) extract (solid-liquid extraction) they.To be after this from solution crystallization, by the separation of centrifugation and the drying of this cake piece.
Another specific embodiments of the present invention will be described in detail by following example.
Example 1: the preparation of lactyllactic acid magnesium and pyrolysis.
With two hydration magnesium lactates (
MG) under atmospheric pressure in 4 hours process, dewatering under 185 ℃.80% the lactic acid (PURAC FCC80) of the anhydride that 20.2g is generated and 22.5g mixes (mortar) fully mutually.Make this uniformly and quite mobile mixture 110 ℃ of reactions 2.5 hours down, this has caused solidifying completely.
This solid of 20.82g is introduced one
In the boiler of glass baking oven B-585, under atmospheric pressure be heated to 100 ℃ (1 hours), 120 ℃ (1 hour), 160 ℃ (40 minutes), and under 6 millibars, be heated to 160 ℃ (1 hours) then.With collected two-part coagulum in straight 2 containers that separate of this boiler, a kind of transparent oily liquids (F1) (analyzing by RMN) of that part of 1.51g of being in the container of the most close this boiler, that part of (4.37g) that collects in a container at last is assumed that and mainly is water and do not analyze simultaneously.
These condensate collecting vessels are replaced with clean container, and distillation continues 2.7 hours under 6 millibars, the setting point with this boiler increases to 280 ℃ from 170 ℃ lentamente simultaneously.
Collected the solid (F2) of 2.19g and analyzed by RMN.
White solid resistates in this boiler adds up to 10.09g (therefore the weight loss of 10.73g taken place).
(% by weight) is as follows for collected analytical results:
The dimer of the LD of F1:3%, 7% lactic acid (LA), 90% LA
The LD of F2:88%, 5% LA dimer, 7% LA
These analytical resultss can be explained as follows:
Two hydration lactyllactic acid magnesium are produced in reaction between the water that a.-brings into by this anhydride and by lactic acid under under atmospheric pressure up to 160 ℃.
B.-is reduced to 6 millibars of distillations that cause free-water with pressure under 160 ℃.
C.-increases to temperature gradually 280 ℃ and causes the lactyllactic acid magnesium dehydration of this hydration and cause it to be decomposed into magnesium hydroxide and rac-Lactide under vacuum, the former is retained in the boiler and the latter mainly is agglomerated among the F2.
Claims (13)
1. method that is used for the cyclic diester of synthetic alpha-hydroxy acid may further comprise the steps:
-alkaline earth salt of the alpha-hydroxy acid of correspondence is mixed with described alpha-hydroxy acid and water;
-mixture is handled by evaporate-crystallization, make the hydrate of linear dimeric alkaline earth salt of alpha-hydroxy acid of described correspondence produce precipitation like this;
-salt of hydration is dewatered to obtain corresponding anhydrous; And
-with described anhydrous salt pyrolysis, thereby discharge described correspondence alpha-hydroxy acid cyclic diester and stay alkaline earth hydroxide as solid residue.
2. according to the described method of above claim, wherein described alkaline earth hydroxide is added in the reaction medium that comprises sugar and bacterium, make like this and pass through the alkaline earth salt that fermentation generates described alpha-hydroxy acid correspondence.
3. according to any one described method in the above claim, wherein said alpha-hydroxy acid is selected from lactic acid, oxyacetic acid, pentanedioic acid, amygdalic acid, oxysuccinic acid, citric acid and tartrate.
4. according to any one described method in the above claim, wherein alkaline-earth metal is selected from Mg, Ca, Zn, Al and Fe.
5. according to any one described method in the above claim, wherein unique principal reaction thing is the aqueous solution of described alkaline earth salt.
6. according to the described method of above claim, wherein described solution is concentrated by evaporation.
7. according to the described method of above claim, wherein half of described spissated solution cooled off, make the hydrate of alkaline earth salt of alpha-hydroxy acid of described correspondence produce precipitation like this.
8. according to the described method of above claim, wherein the salt of described hydration is separated from mother liquor, and further dewatered to obtain described corresponding anhydrous.
9. according to the described method of above claim, wherein with described anhydrous salt in pyrolysis in the presence of water vapour under the temperature of gentleness, thereby discharge described alpha-hydroxy acid and stay described alkaline earth hydroxide as solid residue.
10. according to any one described method in the claim 7 to 9:
-wherein said alpha-hydroxy acid is the steam form, be absorbed in claim 7 spissated solution the second half in, and handle by evaporate-crystallization, make the hydrate of linear dimeric alkaline earth salt of alpha-hydroxy acid of described correspondence produce precipitation like this;
-wherein described hydrate is separated from its mother liquor, and further dewater to obtain corresponding anhydrous;
-wherein with the pyrolysis under the temperature of gentleness of described anhydrous salt, thereby discharge as steam described correspondence alpha-hydroxy acid cyclic diester and stay described alkaline earth hydroxide as solid residue.
11. according to the described method of above claim, wherein be recycled to described alkaline earth hydroxide in the fermentor tank or the alpha-hydroxy acid neutralization reactor in.
12. according to claim 10 or 11 described methods, wherein the steam of the cyclic diester of alpha-hydroxy acid is condensed and carry out in-situ purification by sweating, impurity mainly passes through evaporative removal.
13. according to any one described method in the claim 7 to 9:
-wherein said alpha-hydroxy acid is the liquid or solid form, be separate from described solid residue by distillation or liquid extraction and react with the second half of the spissated solution of claim 7 then, and handle by evaporate-crystallization, make the hydrate of linear dimeric alkaline earth salt of alpha-hydroxy acid of described correspondence produce precipitation like this;
-wherein described hydrate is separated from its mother liquor, and further dewater to obtain corresponding anhydrous;
-wherein with the pyrolysis under the temperature of gentleness of described anhydrous salt, with the cyclic diester of the alpha-hydroxy acid that obtains described correspondence, described cyclic diester as solid or liquid entrainment in alkaline earth metal hydroxides as solid residue; And
-wherein described diester is separated by one or more liquid-solid extraction steps from described solid residue, continue from solution the distillation or crystallize out.
Applications Claiming Priority (3)
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| US865407P | 2007-12-26 | 2007-12-26 | |
| US61/008,654 | 2007-12-26 | ||
| PCT/EP2008/068272 WO2009080834A1 (en) | 2007-12-26 | 2008-12-23 | A process for the production of cyclic diesters of alpha-hydroxyacids |
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| US (1) | US8383835B2 (en) |
| EP (1) | EP2238124B1 (en) |
| JP (1) | JP5444249B2 (en) |
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| EP2102183B1 (en) * | 2006-12-13 | 2012-06-27 | Samuel J. Wajc | Production of cyclic diesters of alpha-hydroxyacids |
| WO2012000921A1 (en) * | 2010-06-29 | 2012-01-05 | Solvay Sa | Process for the manufacture of lactide |
| FR3019463B1 (en) | 2014-04-08 | 2017-06-23 | Tetrahedron | NOVEL ORGANO-SELENED COMPOUNDS, MANUFACTURING METHOD AND PHARMACEUTICAL APPLICATIONS IN PARTICULAR AS ANTI-TUMOR AGENTS |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3429777A (en) * | 1965-09-24 | 1969-02-25 | Harold Eli Bode | High purity magnesium lactate from steepwater |
| US5319107A (en) * | 1990-09-18 | 1994-06-07 | Biopak Technology, Ltd. | Method to produce cyclic esters |
| US5142023A (en) * | 1992-01-24 | 1992-08-25 | Cargill, Incorporated | Continuous process for manufacture of lactide polymers with controlled optical purity |
| US5675021A (en) * | 1992-03-19 | 1997-10-07 | Chronopol, Inc. | Method to produce and purify cyclic esters |
| JP2560259B2 (en) * | 1994-10-21 | 1996-12-04 | 工業技術院長 | Method for producing lactide |
| US5766439A (en) * | 1996-10-10 | 1998-06-16 | A. E. Staley Manufacturing Co. | Production and recovery of organic acids |
| WO2003091238A1 (en) * | 2002-04-25 | 2003-11-06 | Haruo Nishida | Process for producing lactide |
| BE1015060A3 (en) * | 2002-08-06 | 2004-09-07 | Brussels Biotech Nv Sa | Method for producing polylactide departing from a solution of lactic acid or its derivatives. |
| CN1488628A (en) * | 2003-08-01 | 2004-04-14 | 上海高分子材料研究开发中心 | Method for preparing lactide |
| US7705180B2 (en) * | 2004-06-17 | 2010-04-27 | Purac Biochem B.V. | Process for the preparation of lactic acid or lactate from a magnesium lactate comprising medium |
| EP2102183B1 (en) | 2006-12-13 | 2012-06-27 | Samuel J. Wajc | Production of cyclic diesters of alpha-hydroxyacids |
| EP2133346A1 (en) * | 2008-06-12 | 2009-12-16 | Ktanton Ltd | Method of manufacturing a cyclic diester of an alpha-hydroxylated acid |
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